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In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety. In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 every 3 weeks, increasing to 100 mg/m2 from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov, number NCT00545688. Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71–87) for group A, 86% (77–91) for group B, 73% (64–81) for group C, and 73% (63–81) for group D (hazard ratios 0·69 [95% CI 0·34–1·40] group B vs group A, 1·25 [0·68–2·30] group C vs group A, and 2·05 [1·07–3·93] group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72–88) for group A, 84% (72–91) for group B, 80% (70–86) for group C, and 75% (64–83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% [76–91] in patients who achieved total pathological response vs 76% [71–81] in patients who did not achieve total pathological response; hazard ratio 0·54 [95% CI 0·29–1·00]). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 [66%] of 107 patients; group B: 59 [55%] of 107; group C: 40 [37%] of 108; group D: 60 [64%] of 94), febrile neutropenia (group A: 10 [9%]; group B: 12 [11%]; group C: 5 [5%]; group D: 15 [16%]), and leucopenia (group A: 13 [12%]; group B: 6 [6%]; group C: 4 [4%]; group D: 8 [9%]). The number of patients with one or more serious adverse event was similar across groups (19–22 serious adverse events per group in 18–22% of patients). Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer. F Hoffmann-La Roche.

Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m 2, escalating, if tolerated, to 100 mg/m 2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1–55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6–38·5]; p=0·0141). 23 of 96 (24·0% [15·8–33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3–25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients). Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. F Hoffmann-La Roche.

Unreinforced masonry infills are widely used in many parts of the world and it is common practice for seismic design to use simplified methods that usually do not take into account the interaction between the infill and the structure. Starting from the 1950s, many researchers have investigated the lateral response of masonry infills focusing on several different topics. The scientific interest on masonry infills is continuously raising due to the unsatisfactory seismic response of the infilled frame structures observed during post-event inspections and to the difficulty to contrive a widely scientifically and practical recognized solution. Although some modern codes consider the presence of infills with some specifications to prevent damage in the masonry panels and global and local effects on the structure, an effective evaluation of these detrimental effects has not been achieved yet. Within this paper, a FEM simulation of in-plane pseudo-static cyclic tests on a RC frame specimen infilled with unreinforced Autoclaved Aerated Concrete (AAC) masonry infill has been performed in order to study accurately the influence and the interaction of the infill with the RC structure. The experimental results performed by Calvi and Bolognini (J Earthq Eng 5:153–185, 1999), and Penna and Calvi (Campagna sperimentale su telai in c.a. con tamponamenti in Gasbeton (AAC) con diverse soluzioni di rinforzo” (in Italian), 2006) on one-bay one-storey full scale specimens are taken as reference. Non-linear static analyses using a “meso-modelling” approach have been carried out. The masonry used in the model has been calibrated according to tests of mechanical characterization and to in-plane cyclic tests on load-bearing AAC masonry conducted by Costa et al. (J Earthq Eng 15:1–31, 2011). The analyses performed have allowed to investigate the local effects on the frame and, in particular, the changes in the moment and shear demands on the RC elements due to the presence of the AAC infill in comparison with the ones in the bare structure, and to estimate the thrust and the contact length activated by the infill on the frame.

Recent clinical trials demonstrated longer survival in extended small cell lung cancer (SCLC) patients treated with immunotherapy in addition to chemotherapy. However, the magnitude of benefit is modest and the impact in real-world setting has to be fully established. We collected clinical data and radiological imaging of patients affected by extended or relapsing SCLC and consecutively treated according to clinical practice between 2016 and 2023. As primary end-point, we compared pre-defined outcome indicators before and after the introduction of chemo-immunotherapy (May 2020): 6-month and 12-month progression free survival (PFS) rate, 12-month and 18-month overall survival (OS). Among those who were treated after May 2020, patients who did not receive immunotherapy according to treating physician's choice were included in the analysis to minimize clinical selection bias. The analysis included 214 patients: 132 (61.7%) were treated in an Academic cancer center and 82 (38.3%) in two community hospitals; 104 were treated before May 2020. Median PFS of the overall study population was 4.8 months (95% confidence interval [95% CI]: 4.4-5.4), median OS was 7.1 months (95% CI: 6.3-7.7). Estimated PFS and OS were significantly longer in patients treated after May 2020 with hazard ratio (HR) for PFS and OS of 0.61 (95% CI: 0.46-0.81, p < 0.001) and 0.70 (95% CI: 0.52-0.93, p = 0.015), respectively. 6-month PFS rate increased from 27% to 40% (p = 0.04) while 12-months PFS raised from 1% to 11% (p = 0.003). 12-month and 18-month OS rate increased from 15% to 28% (p = 0.03) and from 2.1% to 12% (p = 0.009), respectively. After May 2020 the median number of hospitalization days per patient decreased significantly and the incidence of severe AEs was similar. Among patients treated with chemo-immunotherapy, the onset of immune-related AEs was associated with improved PFS and OS (HR 0.55, 95% CI: 0.35-0.89, p = 0.012 and HR 0.47, 95%CI 0.28-0.77, p = 0.002, respectively). The real-world analysis shows a meaningful improvement of outcome indicators after the introduction of chemo-immunotherapy, with reduction of the duration of hospitalization, thus supporting the use of chemo-immunotherapy and the need for further biomarker research.

Diabetes is an important modifying factor of periodontitis, but its association with peri-implant diseases has not been fully explored and the existing literature reports controversial results. The aim of this retrospective study was to evaluate the influence of diabetes on peri-implantitis and implant failure. Smoking status, history of periodontal disease, presence of diabetes, diabetes type, therapy and glycaemia levels were collected in a total of 204 subjects treated with 929 implants, with a mean follow-up time of 5.7 ± 3.82 years after loading. Odds ratio (OR) for diabetes as a direct cause of peri-implantitis and implant failure were calculated, adjusted for smoking status and history of periodontitis. Nineteen patients were diabetic and most of them presented a good control of the disease at the time of surgery. The overall patient-level prevalence of peri-implantitis was 11.3%. Among diabetic patients, one developed peri-implantitis, whereas one experienced multiple implant failures. The calculated ORs, adjusted for smoking status and periodontitis, were not statistically significant. The results revealed no association between diabetes and peri-implantitis or implant failure coherently with the existing scientific literature. The actual influence of hyperglycemia on implant failure is still uncertain and new studies with larger cohorts of patients are needed.

Clinical practice guidelines (CPGs) recommend against intensive follow-up in asymptomatic women with breast cancer (BC). The present study assessed the adherence to CPGs of diagnostic tests ordering during BC follow-up by exploring routinely collected health data through an algorithm developed to distinguish patients according to their status at follow-up. A retrospective population-based cohort study was performed monitoring the diagnostic tests ordered during 5 years of follow-up in all BC cases incident in 2013 in the Veneto Region, Italy. Data were extracted from the Veneto Tumour Registry, the Hospital Discharge Records and the Outpatients' Records of Diagnostic and Therapeutic Procedures. The algorithm was developed using information on infusion of anticancer agents, imaging exams ordered, and death. The algorithm classified patients by status at follow-up in four groups: (i) probably no-evidence-of-disease (NED), (ii) suspicious signs of relapse not confirmed, (iii) increased risk of relapse and (iv) advanced disease at presentation or progressive disease. A total of 3930 consecutive incident cases were followed-up for 5 years, corresponding to 17,184 person-years, 15,345 of which pertaining to NED cases. In NED cases, 32,900 tumour markers and 15,858 imaging exams were ordered. Liver ultrasonography and chest radiography were most frequently ordered. In contrast with recommendations of CPGs, a substantial overordering of tumour markers and imaging exams occurred in NED BC patients. The developed algorithm can be repeatedly applied to routine health datasets for regular monitoring of the adherence to CPGs and of the impact of interventions to improve appropriateness.

SAM-II is a computer program for seismic nonlinear static (pushover) analysis on new and existing unreinforced (URM), reinforced (RM) masonry and mixed masonry-reinforced concrete (RC) buildings, based on an equivalent frame (EF) modelling approach. The SAM program was originally proposed in the mid-1990s by Magenes and Della Fontana in Proceedings of the British Masonry Society, 1998) and Magenes (in Proceedings of the 12th World Conference in Earthquake Engineering, Auckland, 2000) and was initially conceived for the sole analysis of URM buildings. From the mid-2000s it was completely rewritten in a new code, named SAM-II, and substantially improved. The new program, in fact, also allows for the analysis of RM buildings and mixed RC-masonry structures, the management of semi-rigid floor/roof diaphragms, and the use of new shear strength criteria for masonry elements. The idealization criterion of the adopted EF model and the constitutive laws and strength criteria of the implemented structural elements are presented, focusing on the features of the program implemented in the last 15 years. Some cases of validation of the software, among the most relevant, are presented and discussed. The obtained results confirm that EF models such as SAM-II can be in many cases effective and reliable calculation tools for seismic pushover analyses of masonry buildings, provided the geometry of the building is sufficiently regular in plan and elevation to allow for the EF idealization to simulate its seismic behaviour.

The earthquake sequence started on May 20 th 2012 in Emilia (Italy) affected a region where masonry constructions represent a large part of the existing building stock and the construction of new modern masonry buildings is a common practice. The paper is focused on the performance of common architectural configurations, typical for residential or business use. The large majority of old masonry buildings is made of fired clay bricks. The seismic performance of these buildings is particularly interesting since major past earthquakes in Italy affected areas with mainly stone masonry structures. Apart from examples showing systematic or peculiar structural deficiencies governing the vulnerability of several buildings, the overall seismic performance of these structures to repeated shaking, with PGA as large as 0.25–0.3 g was rather good, despite the major part of them were only conceived for carrying vertical loads. In fact, seismic design is mandatory in the area only since 2003. Modern low-rise masonry buildings erected after this date and incorporating seismic design and proper detailing resulted in most cases practically undamaged. The examples reported in the paper allow an evaluation of the superior performance of seismically designed modern masonry buildings in comparison to older ones.

The traditional construction of masonry infills adjacent to RC structural elements is still widely adopted in European countries, including seismically active regions. Given the repeated field observations from damaging earthquakes, pointing to unacceptably high levels of masonry infill damage, the present study is motivated by the need to improve further the European seismic design approach for new RC structures with masonry infills, in order to exclude the poor seismic behaviour probably caused by deficiencies in the verification procedure. Since the in-plane damage to non-structural panels is commonly controlled through the limitation of inter-storey drifts, the possibility to introduce more effective verification criteria, accounting for structural properties, infill layouts and masonry properties is explored. Therefore, starting from the assumption that analyses and verifications in the design of buildings are commonly accomplished neglecting the presence of infills, results of extensive nonlinear numerical analyses for different building configurations are examined. As a result, a simplified procedure for the prediction of expected inter-storey drifts for infilled structures, based on the corresponding demands of bare configurations, in function of a simple parameter accounting for structural properties and the presence of infills, is introduced. Possible implications of the proposed approach aimed at the improvement of the current design provisions are discussed.

In human epidermis, keratinocyte stem cells (KSC) are characterized by high levels of β1-integrin, resulting in the rapid adhesion to type IV collagen. Since epithelial tumors originate from KSC, we evaluated the features of rapidly adhering (RAD) keratinocytes derived from primary human squamous cell carcinoma of the skin (cSCC). RAD cells expressed higher levels of survivin, a KSC marker, as compared to non-rapidly adhering (NRAD) cells. Moreover, RAD cells proliferated to a greater extent and were more efficient in forming colonies than NRAD cells. RAD cells also migrated significantly better than NRAD cells. When seeded in a silicone chamber and grafted onto the back skin of NOD SCID mice, RAD cells formed tumors 2–4 fold bigger than those derived from NRAD cells. In tumors derived from RAD cells, the mitotic index was significantly higher than in those derived from NRAD cells, while Ki-67 and survivin expression were more pronounced in RAD tumors. This study suggests that SCC RAD stem cells play a critical role in the formation and development of epithelial tumors.